Studies to identify mechanisms for diabetic complications have focused on the toxic effects of hyperglycemia. There has been little work regarding endogenous protective factors that may prevent or neutralize the effects of hyperglycemia. We have characterized a large cohort of patients (Medalists) who have been insulin dependent for 50 or more years. Clinical characterization shows 87% and 35% of Medalists are free of nephropathy and retinopathy. Hemoglobin (Hg) Ale levels, duration, insulin dose, and residual insulin production did not correlate with complication status. In preliminary studies, two types of advanced glycation end products correlated with decreased complications and two with increased levels. Additional biochemical markers, protein kinase 6 and tyrosine phosphatase (SHP-1), correlated with a lack of proliferative diabetic retinopathy (PDR) in those with high HgA1c. Additionally, a pilot follow-up study of Medalists identified a group of subjects protected from PDR. Based on pilot data supporting the presence of endogenous protective factors; we propose three synergistic projects to identify them in this unique cohort. These projects are: 1) Expand, characterize and validate the findings of the Medalist cohort using both longitudinal, cross-sectional and control group studies. The increased sample size (n=1000) will provide the power to statistically relate traditional and novel factors with complication status identified through proteomic (project 1), genetic (project 2), and induced pluripotent stem cell (iPSC) biological studies (project 3). 2) The genetic component will include whole-genome association studies, exomic sequencing, and in collaboration with project 1 the evaluation of the cellular consequences of the abnormalities identified. Findings from projects 1 and 2 will be confirmed in an age-matched control group without diabetes, a younger group of type 1 diabetic patients with and without complications and a pre-existing smaller cohort of diabetic patients in the United Kingdom with similar disease duration as our Medalists. 3) The purpose of this project is to derive and differentiate IPSC from the Medalists and controls (project 1) into fibroblasts, endothelial cells, renal mesangial cells and pericytes. These cells will be exposed to hyperglycemic conditions and factors identified in projects 1 and 2 to determine the differences between who are protected from complications v controls v Medalists those not. The unique qualifies of the Medalists and the combined expertise from leading groups in cell biology, genetics and adult stem cell biology bring extraordinary synergy for identifying protective factors critical in designing therapies for vascular complications in type 1 and 2 diabetic patients. RELEVANCE: The aim of the Medalist Study is to identify factors that can protect diabetic patients from the development of eye and kidney disease in a group of type 1 diabetic patients who have survived with diabetes for more than 50 years without serious development of any eye, kidney or nerve complications.